Phenylpyrimidine amines as ige inhibitors

Abstract

An amine, which is substituted by phenyl-substituted pyrimidin; and phenyl; and a third substituent and its use as an immunoglobulin E (IgE) inhibitor.

1 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is halogen or halo(C 1-4 )alkyl,  
 R 2  is hydrogen, halogen or halo(C 1-4 )alkyl,  
 R 3  is halogen or halo(C 1-4 )alkyl,  
 R 4  is hydrogen, (C 1-8 )alkyl, hydroxy(C 1-6 )alkyl or a group of formula 
 —CO—R 5 ,  
 —CO—(CH 2 ) m —OR 6 ,  
 —CO—CO—R 7 ,  
 —CO—CO—OR 8 ,  
 —CO—N(R 9 R 10 ),  
 —CO—(CH 2 ) n —CO—R 11 ,  
 —CO—(CHR 15 )—O—(CH 2 ) o —CO—R 11 ,  
 —CO—(CH 2 ) p —O—(CH 2 ) q —O—(CH 2 ) r —R 16 ,  
 —CO—O—(CH 2 ) s —O—CO—R 17 ,  
 —CO—O—(CH 2 ) t —N(R 18 R 19 ),  
 —CO—O—(CH 2 ) u —NH—CO—CH(NH 2 )—R 20 , or  
 —CO—O—(CH 2 ) w —NH—CO—R 17 , wherein 
 R 5  is hydrogen, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, aryl or heterocyclyl which is a 5 or 6-membered heterocyclic ring system having 1 to 4 heteroatoms selected from N, O or S,  
 R 6  is hydrogen, (C 1-4 )alkyl, (C 3-8 )cycloalkyl, aryl, (C 1-4 )alkyl substituted by heterocyclyl which is a 5 or 6-membered heterocyclic ring system having 1 to 4 heteroatoms selected from N, O or S, amino(C 1-6 )alkyl, (C 1-4 )alkylamino(C 1-6 )alkyl, di(C 1-4 )alkylamino(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, hydroxy(C 1-4 )alkylamino(C 1-6 )alkyl or an amino acid residue, e.g. —CH 2 —CH(NH 2 )—COOH,  
 R 7  and R 8  independently of each other are (C 1-4 )alkyl, (C 3-8 )cycloalkyl, aryl or heterocyclyl which is a 5 or 6-membered heterocyclic ring system having 1 to 4 heteroatoms selected from N, O or S,  
 R 9  and R 10  independently of each other are hydrogen or (C 1-4 )alkyl or one of R 9  and R 10  is hydrogen and the other is (C 3-8 )cycloalkyl, (C 1-4 )alkyl, aryl or heterocyclyl,  
 R 11  is (C 1-4 )alkyl, —OR 12 , —NR 13 R 14 , an amino acid, an (C 1-4 )alkylester thereof or a di(C 1-4 )alkylester thereof, 
 R 12  is hydrogen or (C 1-4 )alkyl,  
 R 13  and R 14  independently of each other are hydrogen, (C 1-4 )alkyl, amino(C 1-6 )alkyl, (C 1-4 )alkylamino(C 1-6 )alkyl, di(C 1-4 )alkylamino(C 1-6 )alkyl,  
 
 R 15  is hydrogen or (C 1-4 )alkyl,  
 R 16  is hydrogen, (C 1-4 )alkyl, carboxyl or carboxylic ester,  
 R 17  is amino(C 1-4 )alkyl, (C 1-4 )alkylamino(C 1-4 )alkyl or di(C 1-4 )alkylamino(C 1-4 )alkyl,  
 R 18  is hydrogen or (C 1-4 )alkyl,  
 R 19  is hydroxy(C 1-4 )alkyl,  
 R 20  is (C 1-4 )alkyl or hydroxy(C 1-4 )alkyl,  
 m is 0 to 4,  
 n is 2 to 8,  
 o is 0 to 4,  
 p is 0 to 4,  
 q is 1 to 8,  
 r is 0 to 4,  
 s is 1 to 4,  
 t is 1 to 4,  
 u is 1 to 6 and  
 w is 1 to 6.  
 
 
 
     
     
         2 . A compound of  claim 1  wherein 
 —R 1  is chloro or trifluoromethyl,    —R 2  is hydrogen or trifluoromethyl,    —R 3  is chloro, fluoro or trifluoromethyl,    —R 4  is hydrogen, (C 1-4 )alkyl, e.g. methyl, hydroxy(C 1-4 )alkyl, e.g. hydroxyethyl, or a group of formula 
 —CO—R 5 ,  
 —CO—(CH 2 ) m —OR 6 ,  
 —CO—CO—R 7 ,  
 —CO—CO—OR 8 ,  
 —CO—N(R 9 R 10 ),  
 —CO—(CH 2 ) n —CO—R 11 ,  
 —CO—(CHR 15 )—O—(CH 2 ) o —CO—R 11 ,  
 —CO—(CH 2 ) p —O—(CH 2 ) q —O—(CH 2 ) r —R 16 ,  
 —CO—O—(CH 2 ) s —O—CO—R 17 ,  
 —CO—O—(CH 2 ) t —N(R 18 R 19 ),  
 —CO—O—(CH 2 ) u —NH—CO—CH(NH 2 )—R 20 , or  
 —CO—O—(CH 2 ) w —NH—CO—R 17 , wherein 
 R 5  is hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, dimethylamino, phenyl or heterocyclyl which is a 6-membered heterocyclic ring system having one O as a heteroatom, e.g. tetrahydropyranyl,  
 R 6  is hydrogen, (C 1-4 )alkyl, (C 1-2 )alkyl substituted by heterocyclyl which is a 5 or 6-membered heterocyclic ring system having 1 or 2 heteroatoms selected from N or O, e.g. including unsubstituted pyrrolidine, morpholine and piperazine and piperazine substituted by e.g. (C 1-2 )alkyl or (C 1-2 )hydroxyalkyl; amino(C 1-4 )alkyl, (C 1-2 )alkylamino(C 1-4 )alkyl, di(C 1-2 )alkylamino(C 1-4 )alkyl, hydroxy(C 1-3 )alkyl, hydroxy(C 1-2 )alkylamino(C 1-2 )alkyl or an amino acid residue, e.g. —CH 2 —CH(NH 2 )—COOH,  
 R 7  and R 8  independently of each other are (C 1-2 )alkyl or phenyl,  
 R 9  and R 10  independently of each other are hydrogen or (C 1-2 )alkyl,  
 R 11  is (C 1-2 )alkyl, —OR 12 , —NR 13 R 14 , an amino acid, an (C 1-2 )alkylester thereof or an di(C 1-2 )alkylester thereof, preferably an amino acid selected from the group consisting of alanine, phenylalanine, glutamic acid and lysine, wherein the binding is effected via the α-amino group or in the case of e.g. lysine via the ε-amino group, 
 R 12  is hydrogen or (C 1-2 )alkyl,  
 R 13  and R 14  independently of each other are hydrogen, (C 1-2 )alkyl, amino(C 1-4 )alkyl, (C 1-2 )alkylamino(C 1-4 )alkyl, di(C 1-2 )alkylamino(C 1-4 )alkyl,  
 
 R 15  is hydrogen or (C 1-2 )alkyl,  
 R 16  is hydrogen, (C 1-2 )alkyl, carboxyl or carboxylic ester,  
 R 17  is amino(C 1-2 )alkyl,  
 R 18  is hydrogen or (C 1-2 )alkyl,  
 R 19  is hydroxy(C 1-2 )alkyl,  
 R 20  is (C 1-2 )alkyl or hydroxy(C 1-2 )alkyl,  
 m is 0 or 1,  
 n is 2 to 4,  
 o is 0 or 1,  
 p is 0 to 2,  
 q is 2 to 5,  
 r is 0 to 2,  
 s is 2,  
 t is 2,  
 u is 1 to 3 and  
 w is 1 to 3.  
 
   
     
     
         3 . A compound according to  claim 1  which is a compound of formula I wherein 
 R 1  is chloro,    R 2  is hydrogen,    R 3  is trifluoromethyl and    R 4  is hydrogen.    
     
     
         4 . A compound according to  claim 1  which is a compound of formula I wherein 
 R 1  is chloro,    R 2  is hydrogen,    R 3  is trifluoromethyl and    R 4  is a group of formula —CO—O—(CH 2 ) 2 —N[(C 2 H 5 OH)(CH 3 )].    
     
     
         5 . A compound according to  claim 1  in the form of a salt.  
     
     
         6 . (canceled).  
     
     
         7 . A method of treatment of IgE-synthesis-mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic rejection of transplants which method comprises administering a therapeutically effective amount of a compound of  claim 1  to a subject in need of such treatment.  
     
     
         8 . A compound of  claim 1  for use as a pharmaceutical.  
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1  in association with at least one pharmaceutical excipient.  
     
     
         10 . Use of an amine, which is substituted by 
 phenyl-substituted pyrimidin; and    phenyl; and    a third substituent, e.g. R 4  as defined in  claim 1 ,    in the preparation of a medicament for the treatment of IgE-synthesis-mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic rejection of transplants.